Francois Vigneault (Shape Therapeutics)

EX­CLU­SIVE: Shape Ther­a­peu­tics rais­es $112M in bid to make RNA edit­ing — and a whole lot else — a re­al­i­ty

Two years af­ter spin­ning out of CRISPR pi­o­neer Prashant Mali’s lab, Shape Ther­a­peu­tics has a lot more cash and a slight­ly new mis­sion.

The com­pa­ny orig­i­nal­ly launched in 2019 with plans to de­vel­op ther­a­pies around a new form of gene edit­ing, one they hoped could bet­ter ad­dress cer­tain dis­eases than CRISPR or oth­er forms of gene ma­nip­u­la­tions. That’s still their goal, but CEO Fran­cois Vi­gneault has added a few oth­ers in the mean­time.

“The com­pa­ny re­al­ly start­ed as, how can we find a so­lu­tion to some of the lim­i­ta­tions of gene edit­ing?” Vi­gneault said. “But from there, we quick­ly re­al­ized there was a mas­sive bot­tle­neck in an­oth­er sphere of gene ther­a­py.”

Shape end­ed up spend­ing con­sid­er­able time and re­sources try­ing to de­vel­op and make broad­ly avail­able so­lu­tions to two of the biggest con­straints that have held up the broad­er field: man­u­fac­tur­ing and de­liv­ery. They’ll now have a lot more mon­ey to do so and bring for­ward their own med­i­cines, an­nounc­ing a $112 mil­lion Se­ries B on Thurs­day led by Decheng Cap­i­tal and Bre­ton Cap­i­tal.

Shape spe­cial­izes in RNA edit­ing; the com­pa­ny tries to de­vel­op ther­a­pies that in­ter­cept the bro­ken mes­sages that the DNA of pa­tients with cer­tain dis­eases sends out and cor­rect it be­fore it gets turned in­to pro­teins. That con­trasts with CRISPR and oth­er gene edit­ing ap­proach­es that try to di­rect­ly — and per­ma­nent­ly – al­ter DNA.

It does so by ex­ploit­ing a nat­u­ral­ly oc­cur­ring en­zyme that’s al­ready present in hu­man cells called ADAR. By send­ing in their own spe­cial­ly con­struct­ed strand of guide RNA, re­searchers can in the­o­ry re­cruit this en­zyme and get it to ma­nip­u­late spe­cif­ic strands of mes­sen­ger RNA in par­tic­u­lar ways. They could, for ex­am­ple, delete or add bases.

Shape is fo­cus­ing their ef­forts on neu­rons, where ADAR seems to work par­tic­u­lar­ly well — pos­si­bly be­cause it’s nat­u­ral­ly high­ly ex­pressed — and where, by con­trast, CRISPR com­pa­nies have had par­tic­u­lar dif­fi­cul­ty ap­ply­ing their more well-known tech­nol­o­gy. They have lead pro­grams in the rare ge­net­ic dis­ease Rett syn­drome and Parkin­son’s.

In de­vel­op­ing those ther­a­pies, Vi­gneault and his col­leagues ran square in­to the prob­lems every gene ther­a­py com­pa­ny has hit dur­ing the field’s 2010s resur­gence. The vi­ral vec­tors used to shut­tle genes (or in this case, RNA) are dif­fi­cult to man­u­fac­ture at scale. And it’s dif­fi­cult to de­vel­op ones that go pre­cise­ly to the right tis­sue and the right kind of cell in hu­mans.

“We found this [tech­nol­o­gy] is a ma­jor ad­van­tage in neu­rons and CNS dis­or­ders,” Vi­gneault said. “But on the de­liv­ery front what we dis­cov­er is a huge lim­i­ta­tion.”

So Shape en­gi­neered a cell line they claim can pro­duce more ade­no-as­so­ci­at­ed virus (AAV), the most com­mon vi­ral vec­tor used in gene ther­a­py, than any oth­er method. And they in­vest­ed in the tech­nol­o­gy to en­gi­neer AAVs, screen­ing mil­lions of AAVs in cells and mon­keys to de­vel­op ones par­tic­u­lar­ly suit­ed to reach­ing neu­rons or mus­cles.

That puts Shape in di­rect com­pe­ti­tion with com­pa­nies such as Affinia and Dyno, which are ded­i­cat­ed sole­ly to AAV en­gi­neer­ing and have raised hun­dreds of mil­lions of dol­lars and signed bil­lion-dol­lar deals with Big Phar­ma for their vec­tors.

Vi­gneault said Shape will sim­i­lar­ly try to make their AAV and cell lines avail­able to oth­er groups in in­dus­try and acad­e­mia, while con­tin­u­ing to de­vel­op their own ther­a­pies in house and with larg­er com­pa­nies. They have broad am­bi­tions there, too, re­cent­ly up­dat­ing their “pipeline” on­line to show, rather than the few pro­grams clos­est to the clin­ic, a con­stel­la­tion of the dozens of dis­eases they be­lieve their ADAR tech is best suit­ed for, from Alzheimer’s to cys­tic fi­bro­sis.

“The idea is to build a slight­ly dif­fer­ent com­pa­ny than the typ­i­cal one,” Vi­gneault said. “First make a tool that’s dis­rup­tive, not an in­cre­men­tal im­prove­ment, and when you have that tool, make it avail­able so that you can help as many pa­tients as pos­si­ble be­cause one com­pa­ny can’t do it all.”

Cor­rec­tion: The ar­ti­cle has been to clar­i­fy Shape spun out of the Mali lab, not the Church lab.

Stephané Bancel and Ingmar Hoerr (Image created by Endpoints News; Photo credit AP Images)

In Cure­Vac's fail­ure, a pos­si­ble ver­dict on the past (and fu­ture) of mR­NA vac­cines

When three companies emerged in the winter of 2020 promising that a fancy new technology called mRNA could pull the world out of a deadly pandemic, it was easy to overlook the fact that not all mRNA is created equal.

In fact, by the time Covid-19 broke out, the once insular world of mRNA research had split into two rival camps. CureVac, the world’s oldest mRNA company, used the RNA from textbook biology. Four bases or “letters,” spelling out the instructions to make every possible protein. A, U, G, C. But Moderna and BioNTech tinkered with their RNA. If you zoomed into an atomic level, it looked like someone took out one of the letters, flipped half of it on its head and put it back next to the other three, like a famous painting hung upside down on a museum wall.

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US sells Wu-Tang Clan al­bum to cov­er Shkre­li debt; Or­biMed backs GSK vet­s' Chi­nese start­up

Martin Shkreli became a top target for ridicule and anger in the mid-2010s when he and his biotech Turing Pharmaceuticals raised the price of a life-saving medicine from $13.50 to $750 per pill. But he also gained notoriety around that time for purchasing a one-of-a-kind album from rap group the Wu-Tang Clan at auction for about $2 million.

Now, the album is on the move again.

The Department of Justice announced Tuesday it has sold the album, “Once Upon a Time in Shaolin,” to an undisclosed buyer to help cover Shkreli’s $7.36 million debt when he was convicted for defrauding investors in 2017. The sale of the album accounted for the remainder of Shkreli’s balance, the department said in a news release.

Giovanni Caforio, Bristol Myers Squibb CEO (Bristol Myers)

Bris­tol My­er­s' Op­di­vo turns the boat around in Q2 as man­u­fac­tur­ing is­sues haunt CAR-T launch

What a difference a quarter can make.

Stinging from a dip in sales for I/O blockbuster Opdivo last quarter, Bristol Myers Squibb’s top checkpoint inhibitor turned the boat around in Q2, posting 16% growth from the same timeframe in 2020 to $1.91 billion.

On a call with analysts, Bristol Myers execs cited the turnaround to Opdivo’s ongoing gastric cancer launch as well as the inevitable turnaround in prescribing as the Covid-19 pandemic begins to wane. It’s a strong showing for Opdivo despite the fact that the Opdivo combo with CTLA4 inhibitor Yervoy continues turning up red flags.

Covid-19 roundup: As­traZeneca pub­lish­es da­ta on blood clots as­so­ci­at­ed with vac­cine; Glax­o­SmithK­line and Vir ink mAb sup­ply deal with EU

Thirteen cases of thrombosis with thrombocytopenia syndrome in recipients of the AstraZeneca Covid-19 vaccine have led to a number of countries pausing its authorization. On Wednesday, the UK drugmaker published correspondence in The Lancet showing that the estimated rate of TTS in patients who take their first dose of Vaxzevria is 8.1 per million, compared to 2.3 per million for those two weeks after the second dose.

In halt­ing con­fir­ma­to­ry tri­al for On­copep­tides' ac­cel­er­at­ed ap­proval, FDA notes in­creased risk of death

The FDA on Wednesday morning alerted patients and healthcare professionals that the confirmatory trial for Oncopeptides’ multiple myeloma drug Pepaxto (melphalan flufenamide) has been halted, as the combination of Pepaxto and dexamethasone showed an increased risk of death.

The confirmatory trial, required as a condition of Pepaxto’s accelerated approval in February and known as OCEAN, compared Pepaxto and low-dose dexamethasone with Bristol Myers Squibb’s Pomalyst (pomalidomide) with low-dose dexamethasone in patients with relapsed or refractory multiple myeloma, following 2-4 lines of prior therapy and in patients who were resistant to lenalidomide in the last line of therapy.

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Ugur Sahin, BioNTech CEO (Bernd von Jutrczenka/dpa via AP Images)

BioN­Tech is spear­head­ing an mR­NA vac­cine de­vel­op­ment pro­gram for malar­ia, with a tech trans­fer planned for Africa

Flush with the success of its mRNA Covid-19 vaccine, BioNTech is now gearing up for one of the biggest challenges in vaccine development — which comes without potential profit.

The German mRNA pioneer says it plans to work on a jab for malaria, then transfer the tech to the African continent, where it will work with partners on developing the manufacturing ops needed to make this and other vaccines.

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How one start­up fore­told the neu­ro­science re­nais­sance af­ter '50 years of shit­show'

In the past couple of years, something curious has happened: Pharma and VC dollars started gushing into neuroscience research.

Biogen’s controversial new Alzheimer’s drug Aduhelm has been approved on the basis of removing amyloid plaque from the brain, but the new neuro-focused pharma and biotechs have much loftier aims. Significantly curbing or even curing the most notorious disorders would prove the Holy Grail for a complex system that has tied the world’s best drug developers in knots for decades.

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Hal Barron, GSK Investor Day

Glax­o­SmithK­line punts a key Ze­ju­la com­bo study in ovar­i­an can­cer with added set­backs on ICOS and RSV

A chink has appeared in the armor of data that GlaxoSmithKline R&D chief Hal Barron has been building for the PARP inhibitor Zejula.

The pharma giant’s Q2 update on Wednesday includes the note that researchers have ended their Phase II MOONSTONE study, one of a slate of trials that Barron has cited to “help establish Zejula as the most compelling PARP inhibitor for women with ovarian cancer.”

NewAms­ter­dam Phar­ma res­ur­rects Am­gen's old CETP drug with plans to jump in­to PhI­II this year

Eli Lilly thought it found the “holy grail” a decade ago with a CETP inhibitor that lowered bad cholesterol and raised good cholesterol, spurring others like Merck, Amgen, Roche and Pfizer to jump in the race. But when study after study showed the new class of drugs didn’t curb cardiovascular disease, Big Pharma largely abandoned their efforts.

NewAmsterdam Pharma CEO Michael Davidson saw an opportunity last year to resurrect Amgen’s old drug — one of the few that didn’t make it to pivotal studies. And on Wednesday, he unveiled the first positive Phase II results.